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ORIGINAL ARTICLE
Year : 2016  |  Volume : 53  |  Issue : 2  |  Page : 220-225
 

Clinical and pathologic response following taxane based neoadjuvant chemotherapy in locally advanced breast cancer patients in a tertiary care centre in India


1 Department of General Surgery, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, India
2 Department of Radiotherapy, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, India

Date of Web Publication6-Jan-2017

Correspondence Address:
Masillamany Sivasanker
Department of General Surgery, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.197715

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 » Abstract 

Background: Neoadjuvant chemotherapy has become the standard recommendation in the management of patients with locally advanced breast cancer. At present anthracycline based regimen such as CAF (cyclophosphamide, adriamycin and 5-FU) is widely used in clinical practice. The introduction of taxanes has revolutionized this field because of superior results. Aims and Objectives: This study is designed to compare the efficacy of paclitaxel plus doxorubicin regimen and CAF (cyclophosphamide, doxorubicin and 5-fluorouracil) regimen as neoadjuvant treatment of locally advanced breast cancer and to compare their toxicity profiles and also to correlate the hormonal receptor status in predicting response to the NACT. Materials and Methods: In this prospective study, 101 patients with newly diagnosed locally advanced breast cancer were randomized to receive either CAF or Paclitaxel/adriamycin as NACT for three cycles. The response was assessed objectively using CT scans and applying RECIST criteria. The patients were monitored for hematologic, cardiac and other minor toxicities. Results: There was a significantly increased complete and objective response seen in the AP group when compared to CAF group (24% and 58% in the AP group versus 7.8% and 39.2% in the CAF group, P value 0.0313 for complete response). The pCR rate was also significantly higher in the AP group compared to CAF group. (20.93% versus 4.34%, P value 0.0237). There was no significant difference between the groups with respect to cardiotoxicity and hematotoxicity. Patients with ER negative tumors have responded well to neoadjuvant chemotherapy better than ER positive patients. (Objective response 62.8% vs. 40%, P - 0.0473). Conclusions: Based on these results, taxane based regimen such as Paclitaxel/adriamycin can be recommended as a first line neoadjuvant regimen in patients with locally advanced breast cancer.


Keywords: Doxorubicin, locally advanced breast cancer, neoadjuvant chemotherapy, paclitaxel


How to cite this article:
Sivasanker M, Sistla S C, Manwar S A, Vivekanandam S. Clinical and pathologic response following taxane based neoadjuvant chemotherapy in locally advanced breast cancer patients in a tertiary care centre in India. Indian J Cancer 2016;53:220-5

How to cite this URL:
Sivasanker M, Sistla S C, Manwar S A, Vivekanandam S. Clinical and pathologic response following taxane based neoadjuvant chemotherapy in locally advanced breast cancer patients in a tertiary care centre in India. Indian J Cancer [serial online] 2016 [cited 2019 Dec 7];53:220-5. Available from: http://www.indianjcancer.com/text.asp?2016/53/2/220/197715



 » Introduction Top


Neoadjuvant chemotherapy (also called primary systemic therapy or induction therapy) has become a valuable strategy in the multidisciplinary treatment approach to locally advanced breast cancer.[1] Tumor down staging with NACT can convert inoperable disease to operable disease and also facilitates breast conservation surgery.[2] Another advantage is that the chemo sensitivity of the tumor to a particular regimen can be directly assessed by measuring tumor shrinkage following chemotherapy.[3] Despite all these advantages, NACT has not shown any benefit in overall survival.[4] Currently anthracycline based regimens such as CAF (cyclophosphamide, Adriamycin, 5-FU) are the most widely recommended first line regimens in clinical practice for neoadjuvant therapy.[5] The introduction of taxanes has made a major impact in this field because of their superior results.[6] Currently taxane based regimens are mostly favoured as second line agents when the tumor is not responding to conventional CAF regimen and also in metastatic cases. This prospective study had been designed to evaluate the role of taxane based chemotherapy (doxorubicin plus paclitaxel) in the neoadjuvant setting as first line agent and the outcomes and toxicities were compared with the standard CAF regimen in the Indian population. Also several other factors like hormonal receptor status, HER-2/neu expression etc. which seem to have a predictive role in assessing the response to chemotherapy were also assessed in this study.


 » Materials and Methods Top


All newly diagnosed locally advanced breast cancer patients who were candidates for NACT were included in this study. Locally advanced breast carcinoma included patients with T3 (>5 cm) or T4 tumors (chest wall fixation or skin ulceration and/or satellitosis) and N2/N3 disease.[7] Patients with bilateral cancers, recurrent cancer, metastatic disease, pre-existing cardiac illness, pre-existing neuropathy, pregnant or lactating women and patients of childbearing potential not using adequate contraception were excluded from the study. The study was approved by the Institute Ethics committee. All the patients who gave informed consent were included in this study.

Routine history and clinical examination were carried out in all patients. FNAC of the lesion was done to get the diagnosis in all patients. Routine investigations like complete hemogram, renal function tests and liver function tests were done. Metastatic workup was done with chest x-ray and ultrasound abdomen. Core cut biopsy of the tumor was done with 18 G Bard Trucut biopsy needle under local anaesthesia in aseptic conditions. The specimens were preserved in formalin and sent for the assessment of histology, SBR grade,[8] Estrogen and progesterone receptor status and Her2/neu receptor status. Cardiac assessment was done with echocardiogram to assess the left ventricular ejection fraction before starting chemotherapy. Patients were explained about the nature of their illness and the treatment options available to them. Contrast enhanced CT scan of the chest was done to assess the tumor size and for evidence of any lung metastasis before starting chemotherapy. Patients who had lung metastases in CT chest were excluded from the study.

All the patients enrolled in the study were randomized to receive either Paclitaxel/Doxorubicin or Cyclophosphamide/Doxorubicin/5-Fluorouracil regimen as NACT. The doses used in the Taxol group were Paclitaxel – 175 mg/m 2 as a 3 hours IV infusion, Doxorubicin – 50 mg/m 2 as IV infusion. The doses used in the CAF group were cyclophosphamide – 500 mg/m 2 as IV infusion, Doxorubicin 50 mg/m 2 as IV infusion and 5-Fluorouracil – 500/m 2 as IV infusion. Chemotherapy was given on out patient basis after calculating the body surface area and giving antiemetic pre-medications which included Inj Ondansetron 8 mg, Inj dexamethasone 8 mg, Inj Ranitidine 50 mg. The chemotherapy was given as per the regimen after pre-medication and hydration. Patients were observed for immediate side effects like allergic reactions and discharged on the same day with prescriptions for ondansetron tablets, to be taken if they had vomiting.

Chemotherapy was repeated every 21 days after assessing the tumor response clinically for three cycles. Complete hemogram was done prior to each cycle before giving chemotherapy. After two weeks of the last neoadjuvant cycle, tumor size was assessed clinically and a repeat CECT chest was done to assess the size of the residual tumor. RECIST [9] criteria was used to assess the response based on CT scan. According to RECIST criteria, complete response (CR) denotes disappearance of all target lesions. Partial response (PR) denotes at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive disease (PD) denotes at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable disease (SD) denotes neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.

Echocardiogram was repeated to assess for the left ventricular ejection fraction after three cycles of chemotherapy. Any decline in the LVEF was graded according to the ECOG common toxicity criteria.[10] After three cycles of NACT, the patients were worked up for surgery depending on the response and they were operated without any further delay depending on the anaesthetic fitness. Based on the decision taken by the multidisciplinary team including surgeons and radiation oncologists, they were planned for either Modified radical mastectomy (MRM) or Breast conservation therapy (BCT).

The patients were assessed for the incidence of bone marrow toxicity with the complete hemogram during the therapy and any intervention was documented. The degree of bone marrow suppression as evidenced by anemia, leucopenia and thrombocytopenia was graded according to the NCI common toxicity criteria.[11] The patients were also assessed for the incidence of other minor toxicities like nausea, vomiting, alopecia, skin hyperpigmentation, paraesthesias and their degree of severity were also graded according to the NCI common toxicity criteria.[11]

The pathologic response to the NACT was assessed using the histopathological examination of the specimen following surgery. Complete pathologic response (pCR) was defined as no histopathologic evidence of any residual invasive cancer cells in the breast and axillary lymph nodes as per the criteria set by The University of Texas M.D. Anderson Cancer Centre.[12] The various parameters analysed were Age, Menopausal status, T stage, N stage, Tumor Histology, Grade, ER status, PR status, Her2/neu status, Response as graded using RECIST criteria, Pathologic response and the incidence of various toxicities.

Statistical analyses were done using the Statistical Package for Social Sciences software (SPSS, Windows version release 13, SPSS Inc., USA) and unpaired t test done for age analysis. Fisher's exact test and Chi-square test were done for rest of the analyses using the software GraphPad InStat version 3.06, 32 bit for Windows by GraphPad Inc.


 » Results Top


A total of 101 patients who qualified for the inclusion criteria were included in the study and randomly assigned either to the CAF treatment group (n = 51) or the AP (Paclitaxel/doxorubicin) group (n = 50). All the patients received three cycles of NACT. Pre-treatment patient characteristics of the randomly assigned patients (n = 101) were shown in the [Table 1] and were well balanced between the two groups. The mean age of the patients was 50.06 in the CAF group with a range of 27-72 and 48.06 in the AP group with a range of 28-67. In the CAF group, 39 patients (76.5%) had T3 lesion and 12 patients (23.5%) had T4 lesion whereas 33 patients (66%) had T3 lesion and 17 patients (34%) had T4 lesion in the AP group. The histology and grade of the tumor were comparably distributed between the two treatment groups without any significant difference.
Table 1: Pre-treatment patient and tumor characteristics in the two chemotherapy groups

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There was complete disappearance of the tumor in CT scan following NACT in 12 patients (24%) in the AP group as compared to 4 patients (7.8%) in the CAF group which was statistically significant with a P value 0.0313 by Fisher's exact test. (Relative risk = 3.06 and 95% confidence interval = 1.058 to 8.854). 2 patients (4%) had progressive disease in the AP group as compared to 4 patients (7.8%) in the CAF group [Table 2].
Table 2: Response assessed by RECIST criteria in the two chemotherapy groups

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In the AP group, out of the 43 patients who underwent surgery, 14 patients (32.55%) have undergone breast conservation surgery and in the CAF group, out of the 46 patients who underwent surgery, 10 patients (21.73%) have undergone BCS.

The pathologic response was assessed using the final histopathology in those patients who underwent surgery either BCT or MRM. In the AP group, out of the 43 patients who underwent surgery, 9 patients (20.93%) had complete pathologic response without any histologic evidence of invasive tumor cell in the primary tumor as well as in the axillary nodes. In this group 2 patients had in-breast pCR but the axillary nodes showed metastases. In the CAF group, out of the 46 patients who underwent surgery, only 2 patients (4.34%) had complete pathologic response and another 2 patients had in-breast pCR but axillary nodes showed metastases. This difference in the incidence of pCR between the two groups was statistically significant with a P value of 0.0237 by Fisher's exact test and relative risk = 4.814 and 95% confidence interval- 1.101 to 21.043 [Table 3] According to SBR grading of the tumor, among the 11 patients with pCR, preoperatively 3 patients had grade 1 tumor, 5 patients had grade 2 tumor, 1 patient had grade 3 tumor and the grade not known in the remaining 2 patients.
Table 3: Pathologic complete response in the two chemotherapy groups

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In the CAF group, 19 patients (37.3%) had grade 1 cardiotoxicity whereas in the AP group, 14 patients (28%) had grade 1 cardiotoxicity. The incidence of anemia, leucopenia and thrombocytopenia in the two groups are shown in [Table 4]. In the CAF group, 7.8% had grade 3 and another 7.8% had grade 4 anemia respectively. In the CAF group, one patient had grade 4 thrombocytopenia who also had pancytopenia and required GM-CSF injections and blood transfusions. Overall, there was no statistically significant difference in the incidence of hematologic toxicities between the two groups. The incidence of nausea, vomiting, alopecia, skin hyperpigmentation and paresthesias are shown in [Table 4]. In the AP group, around 70% of patients complained of transient mild paraesthesias, which was considered as grade 1 sensory neuropathy. This was statistically significant when compared to CAF group.
Table 4: Incidence of hematologic and other toxicities in the two chemotherapy groups

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Among the 101 patients, 50 patients were ER positive and 43 were ER negative and the ER status was unknown in the remaining 8 patients. Among the ER positive group, 40% of patients showed objective response while in the ER negative group, 62.79% showed objective response to neoadjuvant chemotherapy. Objective response denoted the sum of the complete and partial response cases. This was statistically significant with ER negative tumors responding better to neoadjuvant chemotherapy, (P value - 0.0473) [Table 5]. Among the 11 patients who had complete pathologic response, 6 patients (54.5%) were ER negative. Among the 101 patients studied, 34 patients were HER-2/neu positive, 51 patients were HER-2/neu negative and the HER-2/neu status was unknown in the remaining 16 patients. Among the HER-2/neu positive patients, 55.8% showed objective response while in the HER-2/neu negative group, 49% showed objective response to neoadjuvant chemotherapy. There was no significant difference in response with respect to the HER-2/neu status and the chemotherapeutic regimen (either CAF or AP) which the patients had received.
Table 5: ER receptor status and response according to RECIST

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 » Discussion Top


The introduction of taxanes has made a paradigm shift in the field of neoadjuvant chemotherapy in locally advanced breast cancer.[13] In this study, a better complete and objective response rate was seen in the AP group compared to CAF group. (24% and 58% in the AP arm versus 7.8% and 39.2% in the CAF arm, P value 0.0313 for complete response). This increased response in the AP arm could be definitively attributed to the high anti-tumoral activity of the paclitaxel. In a study involving 200 patients, Dieras et al. have compared doxorubicin plus paclitaxel and doxorubicin plus cyclophosphamide in the neoadjuvant setting and found complete response rates of 15% and 7% in the AP and AC arms respectively.[14] There are variations between different studies in the imaging modality being used and criteria used to assess clinical response. Akashi Tanaka et al. have found CECT to be most accurate for assessing the extent of residual tumor.[15] Moyses et al. have found very high correlation between pre-surgical CT findings and histopathology for residual tumors.[16]

There was a statistically significant higher rate of incidence of pathologic complete response (pCR) in the AP group compared to CAF group (20.93% versus 4.34%, P value 0.0237). Dieras et al. have shown pCR rates of 16% and 10% in the AP and AC arms respectively.[14] In their study, patients with pCR tended to have unifocal disease, tumors with negative receptor status and less differentiation.[14] Kuerer et al. have shown that patients with pCR were more likely to be ER negative and 5 year overall survival was significantly higher in the group which had a pCR (89% vs. 64%).[17] In the NSABP B18 trial using neoadjuvant regimen of doxorubicin and cyclophosphamide, the incidence of pCR was 13% and those patients have showed a superior overall survival of 85% at nine years follow up.[18],[19] Prior to the taxane era, pCR rates were generally below 10% with the anthracycline based regimens as noted in the Indian population.[20] Clearly, with the taxane based neoadjuvant regimens, the pCR rates have exceeded 20% as noted in this study. pCR has been shown to be a surrogate marker for chemotherapy effect even on micro metastases with a definite survival advantage for the patient.[17],[19] Based on these evidences, patients with taxane based chemotherapy definitely have increased chances of pCR and overall survival.

One of the clearly established advantages of neoadjuvant chemotherapy is its ability to convert patients who were initially ineligible for BCT into candidates for this treatment strategy.[2] In this study BCT was performed in 10 patients (21.73%) in the CAF group and in 14 patients (32.55%) in the Taxol group. In those patients who were eligible for BCT, the shrinkage pattern of the tumor could be analysed in CECT following chemotherapy and such cases with pattern 2 shrinkage (shrinkage with residual multinodular lesions) were excluded. Tozaki et al. have shown that MDCT classification of tumor distribution before neoadjuvant chemotherapy and of the shrinkage pattern after chemotherapy was important in the preoperative evaluation for BCT.[21] Investigators from the NSABP B18 trial [18],[19] have documented a recurrence rate of 10.7% following BCT in patients who received preoperative doxorubicin and cyclophosphamide compared to 7.6% in the postoperative group and it has been explained that postlumpectomy local recurrence is one manifestation of aggressive tumor biology and larger tumors are more likely to demonstrate aggressive behaviour even after mastectomy.[18],[19] Newman et al., have analysed the predictors of BCT feasibility following neoadjuvant chemotherapy and shown that features like lobular histology, multicentricity, diffuse calcifications have predicted BCT ineligibility.[2] Typically tumors reduced to 4 cm in size or less are best suited for BCT. With the increased rates of objective tumor response as noted in this study (58%) in the taxol group, patients receiving taxane based chemotherapy have an increased likelihood to become eligible for breast conservation therapy provided the selection is being made according to a strict criteria with multidisciplinary reviews involving surgeons, medical and radiation oncologists.

Chronic cardiotoxicity is the most common type of anthracycline induced myocardial damage and is irreversible and it occurs due to cardiomyopathy.[22] It can usually occur when the cumulative dose of doxorubicin exceeds 300 mg/m 2 in a dose related fashion. In this study, the patients had received only a cumulative dose of 150 mg/m 2 and so they were unlikely to develop any cardiomyopathy. There are reports of unexpectedly high incidence of cardiac toxicity when doxorubicin and paclitaxel are administered together.[23] This worrisome interaction apparently results from paclitaxel's effect on doxorubicin pharmacokinetics with a marked decrease in doxorubicin's clearance rate. But in this study, there was no such incidence of increased cardiotoxicity in the AP group.

The higher incidence of severe anemia in the CAF group (7.8%) when compared to AP group could be due to cyclophosphamide which like most other alkylating agents has got a major suppressive action on the bone marrow progenitor cells.[24] Buzdar et al. have reported a higher fraction of patients (53%) in the paclitaxel arm developing neutropenic fever when a dose of 250 mg/m 2 was given as 24 hours infusion.[25] Compared to these western studies, the lower incidence of hematologic toxicity in our patients could be due to the lower doses of the agents used in the study.

Paclitaxel has been known to cause peripheral neuropathy presenting in a symmetric glove and stocking distribution.[26] We found up to 70% of patients complaining of paraesthesias and this was mostly a transient side effect. Green et al. have reported 76.9% of patients developing paraesthesias after weekly paclitaxel.[27] We did not find any significant difference in the incidence of minor toxicities like nausea, vomiting and alopecia between the two groups. In contrary to the reports in literature stating that major hypersensitivity reactions occur in 3% of patients with paclitaxel,[28] there was no such incidence of allergic reactions in this study. This could probably be due to effective premedication which included dexamethasone 8 mg given intravenously prior to starting the chemotherapy.

It is interesting that, although patients with ER-negative tumors tend to have a worse prognosis, several other investigators also have reported that ER-negative tumors are more likely to be associated with high response rates than that of ER-positive tumors.[17] For the hormone sensitive breast cancer, the concept of neoadjuvant endocrine therapy seems to be emerging with better response rates using aromatase inhibitors.[29]

Approximately 30% of breast cancer patients have HER-2/neu gene amplification and it is associated with higher tumor grade and poorer prognosis.[30] In this study, 33.6% of patients were HER-2/neu positive and there was no difference in the objective response rates between the positive and negative cases. However, data from NSABP B-15 trial [31] had demonstrated that the survival advantage associated with doxorubicin-based chemotherapy appeared to be confined to patients whose tumors overexpress HER-2/neu receptor.


 » Conclusions Top


There has been significantly increased incidence of complete response as well as Pathologic complete response when Paclitaxel/Adriamycin was administered as a first line neoadjuvant regimen, without any overt toxicity when compared to the standard CAF regimen. ER negative tumors tend to respond well with neoadjuvant chemotherapy. Based on these results, taxane based regimen such as Paclitaxel/adriamycin can be recommended as a first line neoadjuvant regimen in patients with locally advanced breast cancer.

 
 » References Top

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Newman LA, Buzdar AU, Singletary SE, Kuerer HM, Buchholz T, Ames FC, et al. A prospective trial of preoperative chemotherapy in resectable breast cancer: Predictors of breast-conservation therapy feasibility. Ann Surg Oncol 2002;9:228-34.  Back to cited text no. 2
    
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Diéras V, Fumoleau P, Romieu G, Tubiana-Hulin M, Namer M, Mauriac L, et al. Randomized parallel study of doxorubicin plus paclitaxel and doxorubicin plus cyclophosphamide as neoadjuvant treatment of patients with breast cancer. J Clin Oncol 2004;22:4958-65.  Back to cited text no. 14
    
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Moyses B, Haegele P, Rodier JF, Lehmann S, Petit T, Velten M, et al. Assessment of response by breast helical computed tomography to neoadjuvant chemotherapy in large inflammatory breast cancer. Clin Breast Cancer 2002;2:304-10.  Back to cited text no. 16
    
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Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 1997;15:2483-93.  Back to cited text no. 18
    
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31.
Paik S, Bryant J, Park C, Fisher B, Tan-Chiu E, Hyams D, et al. erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 1998;90:1361-70.  Back to cited text no. 31
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]

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